Aminodeoxychorismate Synthase Inhibitors from One-Bead One-Compound Combinatorial Libraries: "Staged" Inhibitor Design

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• 作者：Seth Dixon ; Kristin T. Ziebart ; Ze He ; Melissa Jeddeloh ; Choong Leol Yoo ; Xiaobing Wang ; Alan Lehman ; Kit S. Lam ; Michael D. Toney ; Mark J. Kurth
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 14, 2006
• 年：2006
• 卷：49
• 期：25
• 页码：7413 - 7426
• 全文大小：513K
• 年卷期：v.49,no.25(December 14, 2006)
• ISSN：1520-4804

文摘

4-Amino-4-deoxychorismate synthase (ADCS) catalyzes the first step in the conversion of chorismate intop-aminobenzoate, which is incorporated into folic acid. We aim to discover compounds that inhibit ADCSand serve as leads for a new class of antimicrobial compounds. This report presents (1) synthesis of amass-tag encoded library based on a "staged" design, (2) massively parallel fluorescence-based on-beadscreening, (3) rapid structural identification of hits, and (4) full kinetic analysis of ADCS. All inhibitors arecompetitive against chorismate and Mg²⁺. The most potent ADCS inhibitor identified has a K_i of 360 mages/entities/mgr.gif">M.We show that the combinatorial diversity elements add substantial binding affinity by interacting with residuesoutside of but proximal to the active site. The methods presented here constitute a paradigm for inhibitordiscovery through active site targeting, enabled by rapid library synthesis, facile massively parallel screening,and straightforward hit identification.